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MRC Prion Unit
From fundamental research to prevention and cure
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Transgenic modelling of human prion disease, intermammalian transmission barriers and assessment of candidate therapeutics

While the Unit is working to find alternatives to the use of laboratory animals in our research, at this time some crucial work can only be done in mice. Dr Emmanuel Asante and his team have developed a key series of animal models of human prion disease. This involves introducing various forms of the human prion protein gene into mice so that they produce human PrP. This includes both the M and the V form, and such mice are very sensitive to infection with CJD prions and have allowed us to study the various strains of human prions, including notably the strain (known as type 4) which causes variant CJD (vCJD). To date, all confirmed cases of vCJD have been associated with patients with two copies of the M form of the prion protein. To model vCJD, we have generated transgenic models with 2 copies of the M form of the human prion protein and challenged these with the bovine spongiform encephalopathy (BSE), commonly known as “mad cow disease” agent (prions), and we have been able to reproduce the characteristic features of variant CJD seen down the microscope (known as “florid plaques”) in these mice (Figure 1).

Transgenics

Figure 1. Modelling of vCJD in mice. The characteristic pathology of vCJD in human brain –abundant “florid plaques”- is demonstrated in transgenic mice expressing methionine-129 human PrP

Our studies have formed an important part of the evidence showing that variant CJD is the human counterpart of BSE. We also showed for the first time that BSE infection of the M genotype (genetic make up) can lead to an alternate phenotype (outward manifestation of the disease) that looks like sporadic CJD, in addition to the characteristic vCJD features.

Significant as these findings are, people with two copies of the M form of the prion protein constitute only about 38% of the Caucasian population. We have therefore extended our studies to investigate how people with the MV genotype (having one M and one V) who constitute about 51% of the population will be affected by BSE infection.  We have reported that people with the MV genetic make up can also be infected by BSE prions, but the disease will present in a different form from what is known for vCJD so far. In particular, a well established hallmark of variant CJD is the presence of abundant florid plaques in brain sections (Figure 1) that are always linked with the detection of a form of the disease agent described as “type 4 PrPSc”, where PrPSc is the scientific designation for the rogue prion protein. However, our studies with the MV models show that the link between the characteristic brain pathology and type 4 disease agent seen in vCJD patients are no longer maintained.

The transgenic team led by Dr Emmanuel A Asante are also modeling inherited forms of prion disease that are associated with specific mutations (genetic changes) in the prion protein gene. Various genetic mutations are seen in patients with inherited forms of prion disease (also known as familial CJD and GSS). As well as investigating if all inherited forms of prion disease meet the criteria of prion diseases, the team’s modeling work is also aimed at confirming the prediction of the “protein only” hypothesis that inherited prion diseases can occur spontaneously (without any external factors other than having the faulty gene).

All these different types of animal models are being fully characterised and will allow us to test possible treatments for the human prion diseases when other studies ongoing within the Unit reveal suitable therapeutic drugs


Reviews:

Contribution of transgenic models to understanding human prion disease
Wadsworth JDF, Asante EA, Collinge J.  Neuropathol App Neurobiol 2010; 36: 576-97.


Peer reviewed articles:
2015

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology. Acta Neuropathol
Clayton EL, Mizielinska S, Edgar JR, Nielsen TT, Marshall S, Norona FE, Robbins M, Damirji H, Holm IE, Johannsen P, Nielsen JE, Asante EA, Collinge J; FReJA consortium, Isaacs AM.[Epub ahead of print]; PMID: 26358247

Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS. Asante EA, Grimshaw A, Smidak M, Jakubcova T, Tomlinson A, Jeelani A, Hamdan S, Powell C, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Collinge J

A naturally occurring variant of the human prion protein completely prevents prion disease
Emmanuel A. Asante, Michelle Smidak, Andrew Grimshaw1, Richard Houghton, Andrew Tomlinson, Asif Jeelani, Tatiana Jakubcova, Shyma Hamdan, Angela Richard-Londt, Jacqueline M. Linehan, Sebastian Brandner, Michael Alpers, Jerome Whitfield, Simon Mead, Jonathan D.F. Wadsworth and John Collinge. Nature (2015) doi:10.1038/nature14510.

F1000Prime
2013

Atypical scrapie prions from sheep fail to produce disease in transgenic mice overexpressing human prion protein.
Wadsworth JDF, Joiner S, Linehan JM, Balkema-Buschmann A, Spiropoulos J, Simmons MM, Griffiths PC, Groschup MH, Hope J, Brandner S, Asante EA, Collinge J. Emerg Infect Dis 2013; 19: 1731-39.

Inherited Prion Disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein
Asante EA, Linehan JM, Smidak M, Tomlinson A, Grimshaw A, Jeelani A, Jakubcova T, Hamdan S, O’Malley C, Powell C, Brandner S, Wadsworth JDF, Collinge J.  PLoS Pathog 2013; 9(9): e1003643.

2012

 

Overexpression of Hspa13 (Stch) reduces prion disease incubation time in mice
Grizenkovaa J, Akhtara S, Hummerich H, Tomlinson A, Asante EA, Wenborn A, Wiseman FK, Fisher EMC, Tybulewiczc VL, Brandner S, Collinge J, Lloyd SE. Proc Natl Acad Sci USA 2012; 109: 13722-7.

Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice
Ghazi-Noori S, Froud KE, Mizielinska S, Powell C, Smidak M, Fernandez de Marco M, O'Malley C, Farmer M, Parkinson N, Fisher EM, Asante EA, Brandner S, Collinge J, Isaacs AM.  Brain 2012; 135: 819-32. .

2011

 

Interaction between cellular prion protein and toxic Aβ oligomers can be therapeutically targeted at multiple sites
Freir DB, Nicoll AJ, Klyubin I, Panico S, Mc Donald JM, Risse E, Asante EA, Farrow -MA, Sessions RB, Saibil HR, Clarke AR, Rowan MJ, Walsh DM Collinge J. Nat Commun 2011; 2: 336

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study
Wadsworth JDF, Dalmau-Mena I, Joiner S, Linehan J, O'Malley C, Powell C, Brandner S, Asante EA, Ironside JW, Hilton DA, Collinge J.  J Pathol 2011; 223: 511-8.

Threshold for epileptiform activity is elevated in prion knockout mice
Ratte S, Vreugdenhil M, Boult JK, Patel A, Asante EA, Collinge J, Jefferys JG. 
Neuroscience 2011; 179: 56-61.

2010

 

Chronic wasting disease prions are not transmissible to transgenic mice over-expressing human prion protein
Sandberg MK, Al-Doujaily H, Sigurdson CJ, Glatzel M, O’Malley C, Powell C, Asante EA, Linehan JM, Brandner S, Wadsworth JDF, Collinge J.  J Gen Virol 2010; 91: 2651-7.

2009

 

Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins
Asante EA, Gowland I, Grimshaw A, Linehan JM, Smidak M, Houghton R, Osiguwa O, Tomlinson A, Joiner S, Brandner S, Wadsworth JD, Collinge J.  J Gen Virol 2009; 90: 546-58.


Published abstracts
Inherited Prion Disease A117V produces prions that are transmissible to transgenic mice expressing human PrP 117-Valine
Asante EA, Gowland I, Linehan JM, Smidak M, Brandner S and Collinge J. Prion 2010; 4: PPo3-36,156.

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